This Bioengineering Research Partnership (BRP) will exploit emerging advances in semiconductor nanocrystal-based biomedical imaging to probe the tumor microenvironment and to develop therapeutic and diagnostic strategies. To accomplish this, we have assembled a multidisciplinary team of scientists and engineers at the Massachusetts General Hospital (MGH) and Massachusetts Institute of Technology (MIT) with a successful track record of basic and translational research. Over the past decade, this team has provided unprecedented insight into the nature of transport barriers in tumors (Nature Reviews Cancer, 2002). These exciting scientific findings resulted from innovations in intravital imaging (Nature Medicine, 1997, 2001, 2003, 2004), from exploiting molecular tools and quantum dot technology (Nature Medicine, 2005), and from the development of unique in vitro, in vivo, and mathematical models (PNAS, 1998, JCO, 2006). Our discoveries to date have led to novel strategies for improving drug delivery to tumors (Science, 2005). Development Cores led by M. Bawendi (an early pioneer of quantum dots) and D. Nocera at MIT are the corner stone of this BRP. They will develop novel nanocrystal (quantum dot) constructs, biosensors, and immunoconjugates which are not only essential for all three projects in this BRP but also provide a new direction in nanocrystal based bio-imaging by creating "smart" nanocrystal probes of chemical and morphological environment. In Project 1, led by D. Fukumura and L. Munn, we aim to develop "design rules" for nanoparticles and apply these rules to make "smart" nanoparticles that, by changing their size and charge, can circumvent tumor barriers. In Project 2, led by R.K.Jain, we seek to map metabolic microenvironment of tumors with novel nanocrystal based biosensors and improve pH-sensitive chemotherapy and oxygen-sensitive radiation therapy. In Project 3, led by D. Duda and Y. Boucher, we harness the multiplexing capabilities of nanocrystal immunoconjugate probes and biosensors to develop in vivo multi-cell molecular and functional phenotyping techniques and establish a novel treatment strategy based on targeting stromal cells in tumors. A high level of scientific interaction among the three Projects, two Development Cores and four scientific Cores is a major strength of the BRP - as documented in joint publications by Project and Core leaders. Each Project will rely on multi-photon microscopy, mathematical modeling, and statistical support provided by Core A;cutting-edge molecular, cellular and histological expertise provided by Core B;superb surgical and animal support provided by Core C;and administrative support provided by Core D. We also have the resources and the clinical collaborators in place to readily take our scientific findings to clinical trials (Nature Medicine, 2004, Cancer Cell, 2007).